Intraperitoneal administration of 1-(2,5-dimethoxy-4-iodophenyl)-2- aminopropane (DOI) produced significant decreases in the first-hour food intake on day 1 and on day 2 relative to saline-treated animals. Complete tolerance developed to DOI-induced hypophagia by day 3. However, there was no cross-tolerance to m-chlorophenylpiperazine (m- CPP)-induced hypophagia. Similarly, complete tolerance developed to m- CPP-induced hypophagia by day 3, but again there was no cross-tolerance to DOI-induced hypophagia. These findings suggest that DOI and m-CPP- induced hypophagia are mediated by different mechanisms, most likely by selective stimulation of 5-HT2A receptors by DOI and 5-HT2C receptors by m-CPP. In another study, the phenylisopropylamine hallucinogen 1- (2,5- dimethoxy-4-methylphenyl)-2-aminopropane (DOM) produced dose-related increases in plasma concentrations of prolactin, adrenocorticotropic hormone (ACTH) and corticosterone but not growth hormone in rats. By using various 5-HT receptor subtype-selective antagonists, we have demonstrated involvement of 5-HT2A/5-HT2C and 5-HT3 receptors in mediating DOM-induced increases in plasma prolactin, whereas DOM-induced increases in ACTH appear to be mediated by stimulation of 5-HT2A receptors. DOM-induced corticosterone secretion appears to be mediated by stimulation of 5-HT2A and/or 5-HT2C receptors. In a separate series of experiments, the temperature increases induced by either DOI or m-CPP were found to be significantly less in Fawn-Hooded rats (FH) (a rat strain suggested to represent a genetic model of depression and other neuropsychiatric disorders) relative to Wistar rats. Long-term (21 days) treatment with the tricyclic antidepressants, imipramine or clomipramine, attenuated DOI-induced hyperthermia, while m-CPP-induced hyperthermia was accentuated in FH rats. On the other hand, long-term (21 days) treatment with the monoamine oxidase type-A inhibiting antidepressant, clorgyline, did not modify m-CPP-induced hyperthermia, but significantly attenuated DOI-induced hyperthermia in FH rats. These findings demonstrate that long-term antidepressant treatments alter 5-HT2C and 5-HT2A receptor- mediated hyperthermia in a genetic animal model of depression.